Cholecystokinin antagonists useful in the treatment of panic attcks

ABSTRACT

Unnatural dipeptoids of  alpha -substituted Try-Phe derivatives are useful as agents in the treatment of panic disorders. These dipeptoids are CCKB antagonists having utility in the prevention of panic attacks in patients prone to these attacks.

This is a divisional application of U.S. Ser. No. 08/033,062 filed Mar.17, 1993, now U.S. Pat. No. 5,318,981, which is a continuationapplication of U.S. Ser. No. 07/729,271, filed Jul. 12, 1991, nowabandoned.

BACKGROUND OF THE INVENTION

The neuropeptide cholecystokinin-8 (CCK-8) is an importantneuromodulator and neurotransmitter in the brain. There are two types ofCCK receptor which are currently referred to as CCK_(A) and CCK_(B)receptors. The major of the CCK receptor types in brain is the CCK_(B)receptor (Review by Woodruff & Hughes, Annual Review of PharmacologyToxicology 31:469-501 (1991)) .

The functional role of CCK in brain is not fully understood. Recentlythere has been evidence that CCK is involved in anxiety and that CCK_(B)antagonists have an anxiolytic action in animal models of anxiety(Hughes, et al., Proc Natnl Acad Sci, U.S.A. 87:6728-6732 (1990) .

It has recently been shown (de Montigny, C Arch Gen Psychiatry46:511-517 (1989); Bradwejn J, Koszyckl, D, and Metesissian, G, Can JPsychiatr 35:83-85 (1990) that the injection of the tetrapeptidecholecystokinin (30-33) (CCK-4) into human volunteers or into patientssuffering from panic disorder precipitates a panic attack. Thetetrapeptide cholecystokinin (30-33) (CCK-4) is a substance thatstimulates CCK_(B) receptors, i.e., is a CCK_(B) antagonist. Theinjection of tetrapeptide cholecystokinin (30-33) (CCK-4) into thecerebral ventricles of the brain of rats precipitates the onset of ananxiogenic reaction. This anxiogenic response can be prevented bypretreatment of the rats with the CCK_(B) antagonist CI-988 (Sing, etal., Proc Natnl Acad Sci U.S.A. 88:1130-1133 (1991)) .

The present invention relates to compounds known as dipeptoids and/ortheir pharmaceutically acceptable salts for use in the prevention ofpanic attacks in patients prone to these attacks. Suitable compounds arecholecystokinin (CCK)_(B) antagonists such as[R-(R*,R*)]4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid(CI-988) .

The compounds useful in this invention are fully described in Ser. No.07/629,809, filed Dec. 19, 1990, now U.S. Pat. No. 5,278,316. Methods ofpreparing the compounds, intermediates useful in their preparation,compositions containing the compounds, and uses of the compounds aredisclosed. The uses disclosed include the treatment of obesity,hypersecretion of gastric acid in the gut, gastrin-dependent tumors,psychoses, anxiety, ulcer, depression, withdrawal response produced bychronic treatment or use followed by withdrawal from nicotine, diazepam,alcohol, cocaine, caffeine, or opioids.

The disclosure of Ser. No. 07/629,809, now U.S. Pat. No. 5,278,316, isincorporated herein by reference.

SUMMARY OF THE INVENTION

The instant invention concerns a new method of treating panic disorderswhich comprises administering to a human in need of such treatment ortherapeutically effective amount of a compound of formula ##STR1## or apharmaceutically acceptable salt thereof in unit dosage form. R¹, A, R²,R³, R⁴, R⁹, R¹², R¹³, and Ar are as defined below.

The method of the invention is administering the compound in an amountof 0.1 to 20 mg/kg of body weight. A preferred amount is from 1 to 10mg/kg of body weight.

Preferred compounds useful in this method are those of formula I whereinthe cycloalkyl or polycycloalkyl has from about six to ten carbon atomsunsubstituted or substituted with one or more substituents, eachsubstituent selected independently from: methyl, fluorine, chlorine, andbromine.

Other preferred compounds useful in this method are those of formula Iwherein R¹ is cycloalkyl or polycycloalkyl wherein the polycycloalkyl isselected from the group consisting of ##STR2## wherein W, X, Y, and Zare each independently hydrogen, a straight or branched alkyl of fromone to six carbon atoms, CF₃, NR⁵ R⁶, --(CH₂)_(n) CO₂ R*, CN, F, Cl, Br,OR*, SR*, wherein R*, R⁵ and R⁶ are as defined in claim 1 and n is aninteger of from 1 to 3.

A is --NHCO--, OC(═O)--, --SO₂ --, --S(═O)--, --SCO-- or --CH₂ CO--; and

Ar is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3-, or 4-pyridinyl or anunsubstituted or substituted phenyl whose substituents if any are eachindependently hydrogen, fluorine, chlorine, bromine, iodine, methyl,methoxy, trifluoromethyl, nitro, OH, NH₂, OCF₃, NHCOCH₂ CH₂ CO₂ H, orCH₂ CH₂ CO₂ H.

More preferred compounds of the instant invention are those of formula Iwherein in the compound of formula I

R¹ is 2-adamantyl or 1--(S)-2-endobornyl;

A is --NHCO--, --OCO--, --SO₂ --, --S(═O)--, or --CH₂ CO--;

R² is --CH₃, --CH₂ CO₂ H or --CH₂ C.tbd.CH;

R³ is --(CH₂)_(n) --B--D or H;

R⁴ is --(CH₂)_(n) --B--D or H; and

R⁹ is hydrogen or methyl.

Still more preferred compounds of the invention are those of formula Iwherein in the compound of formula I

R¹ is 2-adamantyl, 1--(S)-2-endobornyl, or 2-methyl cyclohexyl,

A is --OC(═O)--;

R² is --CH₃ ;

R³ is H, CH₂ OH, CH₂ OCOCH₂ CH₂ CO₂ H, CH₂ OCOCH═CHCO₂ H, CH₂ NHCOCH₂CN₂ CO₂ H, CH₂ NHCOCH═CHCO₂ H, or CH₂ CO₂ H;

R⁴ is H, --CH₂ SCH₂ CO₂ H, --CH₂ SCH₂ CH₂ CO₂ H, --NHCOCH═CHCO₂ H,--NHCOCH₂ CH₂ CO₂ H ([D] configuration) or NHCOCH═CHCO₂ H [([D]configuration) .

Especially preferred compounds useful in preventing panic attacks or intreating the symptoms of panic are

(±)-trans-2-chlorocyclohexyl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2phenylethyl)amino]ethyl]carbamate;

2-chlorocyclohexyl[2-[[1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-carbamate;

2-[[2-[[[(2-chlorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate;

2-[[2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate;

(±)-tricyclo[3.3.1.1³,7 ]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2- [(2-phenylethyl) amino]ethyl ]carbamate;

(±) or(-)-2-chlorocyclohexyl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate;

tricyclo[3.3.1.1³,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate;

2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl butanedioate;

[R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.37]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]-amino]-4-oxobutanoicacid;

[1S-[1α,2β[S*(S*)],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoicacid;

[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid;

[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]amino]-4-oxo-butanoicacid;

(R)-tricyclo[3.3.1.1³,7]dec-2-yl-[1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl-(2-phenylethyl)amino]-2-oxoethylcarbamate;

[R-(R*,S*)]-2-[[2-[[3-(1M-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfinyl]acetid acid;

[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfonyl]aceticacid;

[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid, ethylester;

[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7[dec-2-yloxy)]carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfonyl]aceticacid;

[R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid;

[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]thio]aceticacid;

[1S-[1α,2β[S*[S*(E)]],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, methyl ester, (bicyclo system is 1S-endo);

[1S-[1α,2β[S*[S*(E)]],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid (bicyclo system is 1S-endo);

[R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-1-phenylethyl]amino]-3-oxopropanoic acid;

[R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxo-8-thia-2,5-diazatridecanoicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl or ester;

[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)-carbonyl]amino]propyl]amino]benzenebutanoic acid;

[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodo-benzenebutanoic acid,where the iodo group may be I-125 or I-127;

[R-(R*,S*)]--N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-4-phenylbutyl]glycine; and

[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid.

A most preferred compound for treating panic disorder symptoms is2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl butanedioate.

DETAILED DESCRIPTION

The compounds useful in the present invention are formed by thecondensation of two modified amino acids and are therefore no peptides.Rather they are "dipeptoids", synthetic peptide-related compoundsdiffering from natural dipeptides in that the substituent group R² isnot hydrogen.

The compounds of the present invention are represented by the formula##STR3## or a pharmaceutically acceptable salt thereof wherein: R¹ is acyclo- or polycycloalkyl hydrocarbon of from three to twelve carbonatoms with from zero to four substituents, each independently selectedfrom the group consisting of: a straight or branched alkyl of from oneto six carbon atoms, halogen, CN, OR*, SR*, CO₂ R*, CF₃, NR⁵ R⁶, or(CH₂)_(n) OR⁵

wherein

R* is hydrogen, straight or branched alkyl of from one to six carbonatoms, R⁵ and R⁶ are each independently hydrogen or alkyl of from one tosix carbon atoms; and

n is an integer from zero to six;

A is (CH₂)_(n) CO--, --SO₂ --, --S(═O)--, --NHCO--, ##STR4## --SCO--,O--(CH₂)_(n) CO-- or --HC--CHCO-- wherein n is an integer from zero tosix;

R₂ is a straight or branched alkyl of from one to six carbon atoms,--HC═CH₂, --C.tbd.CH, --CH₂ --CH═CH₂, --CH₂ C.tbd.CH, --(CH₂)_(n) Ar,--(CH₂)_(n) OR*, --(CH₂)_(n) OAr, --(CH₂)_(n) CO₂ R*, --(CH₂)_(n) NR⁵ R⁶

wherein

n, R' R⁵ and R⁶ are as defined above and Ar is as defined below;

R³ and R⁴ are each independently selected from hydrogen, R² and--(CH₂)_(n) --B--D,

wherein

n' is an integer of from zero to three;

B is a bond ##STR5## wherein R⁷ and R⁸ are independently selected fromhydrogen and R² or together form a ring (CH₂)_(m) wherein m is aninteger of from 1 to 5 and n is as defined above;

D is

--COOR',

'CH₂ OR*,

--CHR² OR*,

--CH₂ SR*,

--CR² SR*,

--CONR⁵ R⁶,

--CN,

--NR⁵ R⁶,

--OH,

--H, and acid replacements such as tetrazole,

and ##STR6## s is an integer of from 0 to 2 wherein R*, R², R⁵, R⁶ andR¹⁰ are as defined above; R⁹ is H, or a straight or branched alkyl offrom one to six carbon atoms, --(CH₂)_(n) CO₂ R*, (CH₂)_(n) OAr',(CH₂)_(n) Ar', (CH₂)_(n) NRSR⁶, wherein n R*, R⁵ and R⁶ are as definedabove or taken from R³ and Ar' is taken from Ar as defined below;

R¹² and R¹³ can each be independently hydrogen (in which case the carbonatom to which it is attached is a chiral center) or can each be takenwith R³ and R⁴ respectively to form a moiety doubly bonded to the carbonatom (in which case the carbon atom is not chiral) and

Ar is a mono- or polycyclic unsubstituted or substituted carbo- orheterocyclic aromatic or hydroaromatic moiety.

Preferred Ar is ##STR7##

Still more preferred Ar is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or4-pyridinyl or an unsubstituted or substituted benzene ring ##STR8##wherein E and F are each independently hydrogen, fluorine, chlorine,bromine, iodine, methyl, methoxy, trifluoromethyl, nitro, hydroxy, NH₂,OCF₃, and R³ as defined above. Preferred definition for R³ is NHCOCH₂CH₂ CO₂ H or CH₂ CH₂ CO₂ H.

The indole portion of formula I can be mono or disubstituted by halogen;lower alkyl; CF₃ ; lower alkoxy; benzyloxy; hydroxy; ##STR9## whereinR¹⁴ is lower alkyl or phenyl; --NO_(2;) NR₁ ¹⁵ R₂ ¹⁶ where R₁ ¹⁵ and R₂¹⁶ are each independently hydrogen or lower alkyl; ##STR10## wherein R¹⁴is as defined above.

Preferred substituents are 5-fluoro, 5-chloro; 5-hydroxy; 5-methyl;5-methoxy; 5-benzyloxy; 5--CF₃, --NO₂ ; and 5-NH₂.

The indole is numbered ##STR11## for purposes of the above substituents.

Further, the indole can be substituted on the nitrogen by-[(4-methylphenyl)sulfonyl] or by a methyl group.

Preferred cycloalkyl or polycycloalkyl substituents have from six to tencarbon atoms.

Preferred compounds of the instant invention are those whereincycloalkyl is a substituted or unsubstituted ##STR12## and whereinpolycycloalkyl is selected from ##STR13## wherein W, X, Y, and S areeach independently hydrogen, a straight or branched alkyl of from one tosix carbon atoms, CF₃, NR⁵ R⁶, --(CH₂)_(n) CO₂ R*, or CN, F, Cl, St,OR*, SR*, wherein R' is hydrogen or a straight or branched alkyl of fromone to six carbon atoms and R⁵ and R⁶ are as defined above and n is aninteger of from 1 to 3.

Other preferred compounds of the instant invention are those wherein

R¹ is 2-adamantyl or 1-(S)-2-endobornyl;

A is --NHCO--, --OCO--, --SO₂ --, --S(═O)- or --CH₂ CO--;

R² is --CH₃, --CH₂ CO₂ CH₃ or --CH₂ C.tbd.CH;

R³ is --(CH₂)_(n),--B--D or H;

R⁴ is --(CH₂)_(n),--B--D or H; and

R⁹ is hydrogen or methyl.

More preferred compounds of the instant invention are those wherein

R1 is 2-adamantyl, 1-(S)-2-endobornyl, or 2-methylcyclohexyl; ##STR14##A is --O--C--, R₂ is --CH₃ ;

R³ is H, CH₂ OH, --CH₂ OCOCH₂ CH₂ CO₂ H, --CH₂ OCOCH═CHCO₂ H or --CH₂NHCOCH₂ CH₂ CO₂ H, or --CH₂ NHCOCH═CHCO₂ H and

R⁴ is H, --CH₂ SCH₂ CO₂ H, --CH₂ SCH₂ CH₂ CO₂ H, --NHCOCH═CHCO₂ H,--NHCOCH₂ CH₂ CO₂ H ([D] configuration or --NHCOCH═CHCO₂ H ((D]configuration) .

The D and the L configurations are possible at the chiral centers d areincluded in the scope of the invention:

1. Preferred is when R² --CH₃ [D_(]) configuration;

2. Preferred is when R³ is --CH₂ OCOCH₂ CH₂ CO₂ H or CH₂ CO₂ H or --CH₂NHCOCH₂ CH₂ CO₂ H with the ID] configuration at the Trp α-carbon atomand the [L] configuration at the Phe-α-carbon atom; d

3. Preferred is when R⁴ is --NHCOCH₂ CH₂ CO₂ H [D] configuration orCOCH═CHCO₂ H[D] configuration with the ID) configuration at the Trpα-carbon atom.

Most preferred compounds of the instt invention are:

1.[1S-[1α,2β[S*[S*(E)]],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid,

2.[1S-[1α,2β[S*(S*)],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]methylamino]-1-phenylethyl]amino]-4-oxobutanoicacid,

3.[1S-[1α,2β[S*(S*)],4]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-2.2.1]hept-2-yl)amino]carbonyl]amino]propyl]ino]-1-phenylethyl]amino]-4-oxobutanoicacid,

4.[R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[3.3.1.1.sup.3,7]dec-2-ylsulfonyl)amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoicacid,

5.JR-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[(tricyclo[3.3.1.1.sup.3,7]dec-2-ylsulfonyl)amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

6. [1R-[1α[R*(S*)],2β]]and[1S-[1α[S*(R*)],2β]]-4-[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

7. [1R-[1α[R*(S*)],2β]]and[1S-[1α[S*(R*)],2β]]-4-[2-[[2-[[[(2-fluorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

8. [1R-[1α[R*(S*)], 2β]] and[1S-[1α[S*(R*)],2β]-4-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

9. [1R-[1αR*(S*)],2β]] and[1S-[1α[S*(R*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[[2-(trifluoromethyl)cyclohexyl]oxy]carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

10.[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]methylamino]-3-phenylpropyl]amino]-4-oxobutanoicacid,

11.[1S-[1α,2β[S*(R*)],4α]]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-1-(phenylmethyl)ethyl]amino]ethyl]carbamicacid, 1,7,7-trimethylbicyclo[2.2.1]hept-2-yl ester,

12.[1S-[1α,2β[S*(R*)],4α]]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazo1-5-yl)-propyl]amino]-2-phenylethyl]amino]ethyl]carbamicacid, 1,7,7-trimethyl-bicyclo [2.2.1]hept-2-yl ester,

13. N-[2-methyl-N-[(tricyclo[3.3.1.1³,7 ]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,

14. N-[2-methyl-N-[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl-β-alanine and

15. (R)-tricyclo[3.3.1.1³,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxoethylcarbamate.

In addition most especially preferred compounds of the instant inventionare:

16.(±)-Trans-2-chlorocyclohexyl[1-(1H-indol-3-yl-methyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate,

17.2-chlorocyclohexyl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,

18.2-[[2-[[[(2-chlorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate,

19.2-[[2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate,

20. (±)-tricyclo[3.3.1.1³,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethylcarbamate,

21. tricyclo[3.3.1.1³,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-yl-methyl)-1-methyl-2-oxoethyl]carbamate,

22. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl butanedioate,

23. 2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-1-phenylethyl butanedioate,

24.-[R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,

25.[1S-[1α,2β[S*(S*)],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoicacid,

26.[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid,

27.[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxobutanoic acid,

28. (R)-tricyclo[3.3.1.1³,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxoethylcarbamate,

29.[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]aceticacid, ethyl ester,

30.[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]aceticacid, ethyl ester,

31.[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,

32.JR-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid,

33.[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]aceticacid,

34.[1S-[l,2[S*[S*(E)]],4i]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, methyl ester, (Bicyclo system is 1S-endo),

35.[1S-[1α,2β[S*[S*(E)]],4]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, (Bicyclo system is 1S-endo) ,

36.[R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-3-oxo-propanoicacid,

37.[R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxo-8-thia-2,5diazatridecanoicacid, tricyclo[3.3.1.1³,7 ]dec-2-yl or ester,

38.[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]benzenebutanoic acid,

39.[R-(R*,S*)]-N-J3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-4-phenylbutyl]glycine,

40. [R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]-amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid,

41. mono[R-(R*,R*)]-2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-1-phenylethyl butanedioate,

42. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]propanoicacid (TRP is R, other center is RS),

43.[1R-[I[R*(S*)],β2]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid, (-)-Isomer,

44.[1R-[1α[R*(S*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-3-phenylpropyl]amino]-4-oxobutanoicacid, (-)-Isomer,

45.[1R-[1α[R*(S*)],2β]]-4-[[2-[[3-(lH-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, (-)-Isomer,

46.[1R-[1α[R*(S*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-1-phenylethyl]amino]-4-oxobutanoicacid, (-)-Isomer,

47.2-methylcyclohexyl-[1R-[1α[R*(S*)]],2β]-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(IH-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,

48.[R-[R*,S*-(E,E)]]-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3-3-1.1³,7]dec⁻ 2-yloxy)carbonyl]amino]propyl]-amino]-7-phenyl-2,4-heptadienoicacid,

49.[R-(R*,R*)]-[2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)-butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid,

50. tricyclo-[3.3.1.1³,7]dec-2-yl-[S-[R*,S*-(E)]]-12-(1H-indol-3-ylmethyl)-12-methyl-3,11-dioxo-9-(phenylmethyl)-2-oxa-7,10,13-triazatetradec-4-en-14-oate,

51.[R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]-amino]-3-phenylpropyl]amino]-3-oxopropanoicacid,

52.ethyl[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]thio]acetate,

53.[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-4-iodo-benzenebutanoic acid,

54.[R-(R*,R*)]-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(1(tricyclo[[(3.3.1.1³,7]dec-2-yloxy)-carbonyl]amino]-propyl]amino]-1-phenylethoxy ]acetic acid,

55. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo(3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]acetic acid (TRPcenter is R, other center is RS) ,

56. (R)-[[[2-[[3-(1H-indol-3-yl)-1-oxo-2-methyl-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethylidene]amino]oxy]acetic acid,

57.[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]-amino]benzenebutanoic acid,

58.[R-(R*,S*)]--N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy)carbonyl]propyl]amino]-4-phenylbutyl]glycine,

59. 2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec⁻ 2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylicacid (cyclopropane ring is trans-(±) other centers are R),

60. carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]-amino]ethyl]-, tricyclo[3.3.1.1³,7]dec-2-yl ester, [R, (R*,S*]-,

61. benzeneheptanoic acid,α-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-, [R-(R*,S*)]-,

62.methyl-(±)-β-[[(2-phenylethyl)amino]carbonyl]-1β-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]-1H-indole-3-butanoate,

63.[R-(R*,S*)]-4-[[2-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1.sup.3,7]dec-2-yloxylcarbonyl]amino]propyl]-amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid,

64. bicyclo[2.2.1]heptane-2-acetic acid,3-[[[[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indo1-3-ylmethyl)-1-methyl-2-oxoethyl]amino]carbonyl]oxy]-4,7,7-trimethyl-,[1R-[1α,2β,3α[R*(S*)], 4α]]-,

65. butanoic acid,4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-1R-[I[R*(R*)]2]]-((-)-isomer),

66. 2-butenoic acid,4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-1-pheny1 ethyl]amino]-4-oxo-1R-[I[R*(R*)],2]]-((-)-isomer) ,

67. butanoic acid,4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-3-phenylpropyl]amino]-4-oxo-[1R-[1α[R*(S*)],2β]]-((-)-isomer),and

68. 2-butenoic acid, 4-[[2-[[3-)1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]-amino]-3-phenylpropyl]amino]-4-oxo-[IR[1α[R*(S*)],2β]]-((-)-isomer).

Additionally preferred are the compounds:

69. [[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]aceticacid (TRP center is R, other center is RS),

70.[R-(R*,R*)]-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-1phenylethoxy]acetic acid,

71.[1R-[1α,2β[R*(R*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylic acid,

72.[1S-[1α,2β[S*(S*)]]]-2-[[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]cyclopropanecarboxylic acid,

73.[R-R*,R*)]-3-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethoxy]propanoic acid,

74. [R-(R*,R*)]-mono2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]-1-phenylethyl butanedioic acid,

75. 3-[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-2-phenylpropyl]amino]propanoic acid,(TRP is R, other center is RS),

76.[R-(R*,S*)]--[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-4-iodobenzenebutanoic acid,

77.[1R-[1αR*(S*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid, ((-)-isomer) ,

78.[1-([1α[R*(S)],(S)*2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1cyclohexyl)oxy]carbonyl]-amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxobutanoicacid, ((-)-isomer),

79.[1R-[1α[R*(R*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, ((-)-isomer),

80.1R-[1α[R*(R*)],2β]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[[(2-methyl-1-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-1-phenylethyl]amino]-4-oxobutanoicacid, ((-)-isomer),

81.[R-(R*,S*)]-1δ-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]benzeneheptanoic acid,

82. 2-[[[2-[[3-(1M-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]carbonyl]-cyclopropanecarboxylicacid (cyclopropyl ring is trans-(±), other centers are R),

83.2-methylcyclohexyl[1R-[I[R*(S*)]],2]-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate,((-)-isomer,

84.[R-[R*,S*-(E,E)]]-6-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-7-phenyl-2,4-heptadienoicacid,

85. tricyclo[3.3.1.1³,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-hydroxy-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methylethyl]carbamate,

86. tricyclo[3.3.1.1³,7]dec-2-yl[R-(R*,R*)]-[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[1-oxo-3-(1H-tetrazol-5-yl)propyl]amino]-2-phenylethyl]amino]ethyl]carbamate,

87.[R-(R*,S*)]-2-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]-amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid,

88.[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-y.loxy)]ca═bonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]aceticacid,

89. Ethyl[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricycl o [3.3.1.1³,7]dec-2-yloxy)]carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfonyl]acetate

90.2-chlorocyclohexyl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2 -oxoethyl]carbamate, Isomer II, ring centers aretrans, trp center is D, other center is S) ((-) or (+) form),

91. JR-[R*,R*(E)]]-4-[[2-[[3-(1M-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7 ]dec-2ylamino)carbonyl]amino]propyl]amino]-1phenylethyl ]amino]-4-oxo-2-butenoic acid,

92.[R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid,

93.[R-(R*,S*)]-mono[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl]butanedioate,

94. tricyclo[3.3.1.1³,7]dec-2-yl[R-(R*,S*)-2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-carbamate,

95.[1S-[1α,2[S*[S*(E)]],4]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]-propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid (bicyclo system is 1S-endo),

96.[1S-[1α,2[S*(S*)],4]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-y 1 )oxy]carbonyl]-amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid (bicyclo system is 1S-endo),

97.[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid,

98. N-[2-methyl--N-[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanylglycine,

99.[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-4oxobutanoic acid,

100.[R-(R*,R*)]-[2-[[2-[[1,4-dioxo-4-(1H-tetrazol-5-ylamino)butyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamicacid,

101.[R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-3-oxopropanoic acid,

102.[R-(R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-3-oxopropanoic acid,

103. [R-[R*,S* [(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo[3.3.1 ]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid,

104.[R-[R*,S*)]-5-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]amino]-5-oxopentanoic acid,

105.ethyl[R-(R*,S.sup.)]-[[2-[[3-(1H-indo1-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)-carbonyl]amino]propyl]amino]-3-phenylpropyl]sulfinyl]acetate,106.[R-(R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoic acid,

107.[R-(R*,S*)]--N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-oxo-4-phenylbutyl]-β-alanine,

108. N-[N-[-methyl--N-[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]-D-tryptophyl]-L-phenylalanyl]-L-alanine,

109.[R-R*,S*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]propanoicacid,

110.[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]-3-phenylpropyl]thio]aceticacid,

111.[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]amino]benzenebutanoic acid,

112. tricyclo[3.3.1.1³,7]dec-2-yl[R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxa-8-thia-2,5-diazatridecanoic acid,

113. Carbamic acid,[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methyl-1-[(1-methyl-1H-indol -3-yl)methyl]-2-oxoethyl]-, tricyclo[3.3.1.1³,7]dec-2-yl ester, JR-(R*,S*)]-,

114. Glycine,N-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]-N-(2-phenylethyl)--, (±)-,

115. Glycine,N-[3-(1H-indo1-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl]-N-(2-phenylethyl)-, methyl ester,(±)-,

116. Methyl(±)-7-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]amino]propyl](2-phenylethyl)amino]heptanoate,

117. (±)-7-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxycarbonyl]amino]propyl](2-phenylethyl)amino]heptanoic acid,

118. Carbamic acid, [2-[[2-(1-cyclohexen-1-yl)ethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-, (R)-,

119. Carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-(2-pyri diny 1 ) ethyl]amino]ethyl]-, tricyclo[3.3.1.1³,7 ]dec-2-yl ester,(R)-,

120. Benzenebutanoic acid,4-amino--[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-, [R-(R*,S*)]-,

121. Acetic acid,[[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy) carbonyl]-amino]propyl]amino]-2-phenylpropyl]thio]- (TRPcenter is R, other center is RS),

122. 12-oxa-9-thia-2,5-diazatetradecanoic acid,3-(1H-indol-3-ylmethyl)-3-methy 1-4,11-dioxo-7-phenyl-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester (TRP center is R, other center isRS),

123. Benzenebutanoic acid,γ-[[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]methyl]-(TRP center is R, othercenter is RS),

124. 2-pentenoic acid,5-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7 ]dec-2-y 1oxy ]carbon yl]amino]propyl]amino]-4-phenyl-, methyl ester (TRP centeris R, other center is RS, double bond is (E)),

125. Benzenebutanoic acid,γ-[[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]methyl]-, methyl ester (TRPcenter is R, other center is RS),

126. Butanoic acid,4-[[2-[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]ethyl]phenyl]amino]-4-oxo-,(R)--,

127. Carbamic acid,[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[[2-[[[(1H-1,2,4-triazol-5-ylthio)acetyl]amino]-2-phenylethyl]amino]ethyl]-,tricyclo-[3.3.1.1³,7 ]dec-2-yl ester, [R-(R*,R*)]-,

128. Carbamic acid,[2-[[2-[[(1H-imidazol-2-ylthio)acetyl]amino]-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester, [R-(R*,R*)]-,

129. Butanoic acid,4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3-1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-,(Phenyl center R, other center S or R) (Diastereomer II),

130. Butanoic acid,4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-(Phenylcenter R, other center R or S) (Diastereomer I),

131. 13-oxa-2,5,8-triazatetradecanoic acid,3-(1H-indol-3-ylmethyl)-3-methyl-4,9,12-trioxo-7,14-diphenyl-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester (Phenyl center is R, other center isS or R) (Diastereomer 2),

132. 13-oxa-2,5,8-triazatetradecanoic acid,3-(1H-indol-2-ylmethyl)-3-methyl-4, 9, 12-trioxo-7,14-diphenyl-,tricyclo[3.3.1.1³,7 ]dec-2-yl ester (Phenyl center is R, other center isR or S) (Diastereomer 1),

133. Carbamic acid,[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-2-ylmethyl)-1-methyl-2-oxoethyl]-, tricyclo[3.3.1.1³,7 ]dec-2-yl ester(Hydroxymethyl center is S, other center is R or S) (Diastereomer 1),

134. Carbamic acid,[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1(1H-indol-2-ylmethyl)-1-methyl-2-oxoethyl]-, tricyclo[3.3.1.1³,7 ]dec-2-yl ester(Hydroxymethyl center is S, other center is S or R) (Diastereomer 2),and

135. Carbamic acid,[1-methyl-i-[[1-[(4-methylphenyl)sulfonyl]-1H-indol-2-yl]methyl]-2-oxo-2-[(2-phenylethyl)amino]ethyl],tricyclo[3.3.1.1³,7 ]dec-2-yl ester, (±)-.

In addition to the compounds above the compounds of the presentinvention include compounds of formula I wherein the indole moiety is a2-indolyl.

The compounds include solyates and hydrates and pharmaceuticallyacceptable salts of the compounds of formula I.

Preferred pharmaceutically acceptable salts are benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium,zinc, diethylamine, and tromethane.

Especially preferred pharmaceutically acceptable salts areN-methylglucamine and sodium.

The compounds of the present invention can have multiple chiral centersincluding those designated in the above formula I by an depending ontheir structures. For example, when R³ taken with R¹² and R⁴ taken withR¹³ form double bonds to these carbon atoms they are no longer chiral.In addition, centers of asymmetry may exist on substituents R¹, R⁹, R³,R⁴ and/or Ar. In particular the compounds of the present invention mayexist as diastereomers, mixtures of diastereomers, or as the mixed orthe individual optical enantiomers. The present invention contemplatesall such forms of the compounds. The mixtures of diastereomers aretypically obtained as a result of the reactions described more fullybelow. Individual diastereomers may be separated from mixtures of thediastereomers by conventional techniques such as column chromatographyor repetitive recrystallizations. Individual enantiomers may beseparated by convention method well known in the art such as conversionto a salt with an optically active compound, followed by separation bychromatography or recrystallization and reconversion to the nonsaltform.

The compounds of the present invention can be formed by couplingindividual substituted -amino acids by methods well known in the art.(See, for example, standard synthetic methods discussed in themulti-volume treatise "The Peptides, Analysis, Synthesis, Biology," byGross and Meienhofer, Academic Press, New York.) The individualsubstituted alpha amino acid starting materials are generally known or,if not known, may be synthesized and, if desired, resolved by methodswithin the skill of the art. (Synthesis of racemic [DL]-α-methyltryptophan methyl ester--see Braa, M. F., et al., J. Heterocyclic Chem.,1980, 17:829.)

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents it can also be an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository preparations, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

The powders and tablets preferably contain 5 to about 70% of the activecomponent. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth,methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax,cocoa butter, and the like.

The term "preparation" is intended to include the formulation of theactive component with encapsulating material as a carrier providing acapsule in which the active component (with or without other carriers)is surrounded by a carrier which ie thus in association with it.Similarly, cachets are included.

Tablets, powders, cachets, and capsules can be used as solid dosageforms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid preparations can also beformulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolvingthe active component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

Preferably the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is divided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofthe preparation, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

The dipeptoids, their pharmaceutically acceptable salts, hydrates, andsolyates are administered to mammals, e.g., humans.

The diagnosis of the group of disorders covered herein is thepredominant disturbance as in Panic Disorder as in the thirdedition-revised of the Diagnostic and Statistical Manual Of MentalDisorders (DSM-111-R), published by the American Psychiatric Association(1987) .

Pharmaceutical Formulations

In the following examples of pharmaceutical formulations according tothe present invention, unless otherwise indicated, the term "ActiveIngredient" represents a dipeptoid of the invention hereinbefore definedor a pharmaceutically acceptable salt thereof. The dose represents thatappropriate for the base; if a salt is used the dose should of course beincreased appropriately.

EXAMPLE 1

    ______________________________________                                        Tablet                                                                                         Amount per                                                   Ingredient       tablet (mg)                                                  ______________________________________                                        Active Ingredient*                                                                             60.0                                                         Lactose          125.0                                                        Corn Starch      50.0                                                         Polyvinylpyrrolidone                                                                           3.0                                                          Stearic acid     1.0                                                          Magnesium stearate                                                                             1.0                                                          ______________________________________                                         *[R(R*,R*)4-[[2[[3(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1.sup    3.7 ]dec2-yloxy)carbonyl]amino]propyl]amino1-phenylethyl]amino4-oxobutanoi     acid                                                                     

EXAMPLE 2

    ______________________________________                                        Capsule                                                                                        Amount per                                                   Ingredient       capsule (mg)                                                 ______________________________________                                        Active Ingredient*                                                                              60.0                                                        Lactose          174.0                                                        Corn Starch      174.0                                                        Stearic acid      2.0                                                         ______________________________________                                         *[R(R*,R*)4-[[2[[3(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1.sup    3.7 ]dec2-yloxy)carbonyl]amino]propyl]amino1-phenylethyl]amino4-oxobutanoi     acid                                                                     

EXAMPLE 3

    ______________________________________                                        Ampoule                                                                                         Amount per                                                  Ingredient        ampoule                                                     ______________________________________                                        Active Ingredient*                                                                              60.0 mg                                                     Water for injection, q.s.                                                                       1.0 mL                                                      ______________________________________                                         *[R(R*,R*)4-[[2[[3(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1.sup    3.7 ]dec2-yloxy)carbonyl]amino]propyl]amino1-phenylethyl]amino4-oxobutanoi     acid                                                                     

EXAMPLE 4

    ______________________________________                                        Suppository                                                                                        Amount per                                               Ingredient           suppository                                              ______________________________________                                        Active Ingredient*   60.0 mg                                                  Theobroma oil (cocoa butter), q.s.                                                                 2.0 g.sup.                                               ______________________________________                                         *[R(R*,R*)4-[[2[[3(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1.sup    3.7 ]dec2-yloxy)carbonyl]amino]propyl]amino1-phenylethyl]amino4-oxobutanoi     acid                                                                     

I claim:
 1. A method of treating a panic disorder in a human who hasbeen identified as exhibiting panic disorder symptoms which comprisesadministering to said human a therapeutically effective amount of acompound of formula ##STR15## or a pharmaceutically acceptable saltthereof wherein: a cyclo- or polycycloalkyl hydrocarbon of from three totwelve carbon atoms with from zero to four substituents, eachindependently selected from the group consisting of: a straight orbranched alkyl of from one to six carbon atoms, halogen, CN, OR* SR*,CO₂ R*, CF₃, NR⁵ R⁶ or (CH₂)_(n) OR⁵ wherein R* is hydrogen, straight orbranched alkyl of from one to six carbon atoms, R⁵ and R⁶ are eachindependently hydrogen or alkyl of from one to six carbon atoms; and nis an integer from zero to six;A is (CH₂)_(n) CO--, --SO₂ --, --S(═O)--,--NHCO--, ##STR16## --SCO--, O--(CH₂)_(n) CO-- or --HC═CHCO-- wherein nis an integer from zero to six; R₂ is a straight or branched alkyl offrom one to six carbon atoms, --HC═CH₂, --C.tbd.CH, --C₂ --CH═CH₂, --CH₂C═CH, --(CH₂)_(n) Ar, --(CH₂)_(n) OR*, --(CH₂)_(n) OAr, --(CH₂)_(n) CO₂R*, or --(CH₂)_(n) NR⁵ R⁶ wherein n R' R⁵ and R⁶ are as defined aboveand Ar is as defined below; R³ and R⁴ are each independently selectedfrom hydrogen R² and --(CH₂)_(n), --B--D wherein n' is an integer offrom zero to three; B is a bond, ##STR17## wherein R⁷ and R⁸ areindependently selected from hydrogen and R² or together form a ring(CH₂)_(m) wherein m is an integer of from 1 to 5 and n is as definedabove; D is--COOR', 'CH₂ OR*, --CHR² OR*, --CH₂ SR*, --CR² SR*, --CONR⁵R⁶, --CN, --NR⁵ R⁶, --OH, --H, and acid replacements: ##STR18## s is aninteger of from 0 to 2 wherein R*, R², R⁵, R⁶ and R¹⁰ are as definedabove; R⁹ is H, or a straight or branched alkyl of from one to sixcarbon atoms, --(CH₂)_(n) CO₂ R*, (CH₂)_(n) OAr', (CH₂)_(n) Ar',(CH₂)_(n) NR⁵ R⁶, wherein n, R*, R⁵, and R⁶ are as defined above ortaken from R³ and Ar' is taken from Ar as defined below; R¹² and R¹³ caneach be independently hydrogen in which case the carbon atom to which itis attached is a chiral center, or can each be taken with R³ and R⁴respectively to form a moiety doubly bonded to the carbon atom in whichcase the carbon atom is not chiral; and Ar is a mono- or polycyclicunsubstituted or substituted carbo- cyclic aromatic or hydroaromaticmoiety.
 2. A method according to claim 1 wherein the amount is 0.25 to15 mg/kg of body weight.
 3. A method according to claim 1 wherein theamount is 1 to 10 mg/kg of body weight.
 4. A method according to claim 1wherein in the compound of formula I the cycloalkyl or polycycloalkylhas from about six to ten carbon atoms unsubstituted or substituted withone or more substituents, each substituent selected independently from:methyl, fluorine, chlorine, and bromine
 5. A method according to claim 1wherein in the compound of formula I R¹ is cycloalkyl or polycycloalkylwherein the polycycloalkyl is selected from the group consisting of##STR19## wherein W, X, Y, and Z are each independently hydrogen, astraight or branched alkyl of from one to six carbon atoms CF₃, NR⁵ R⁶,--(CH₂)_(n) CO₂ R*, CN, F, Cl, Br, OR*, SR*, wherein R*, R⁵ and R⁶ areas defined in claim 1 and n is an integer of from 1 to 3;A is --NHCO--,OC(═O)--, --SO₂ --, --S(═O)--, --SCO-- or --CH₂ CO--; and Ar is anunsubstituted or substituted phenyl whose substituents if any are eachindependently hydrogen, fluorine, chlorine, bromine, iodine, methyl,methoxy, trifluoromethyl nitro, OH, NH₂, OCF₃, NHCOCH₂ CH₂ CO₂ H, or CH₂CH₂ CO₂ H.
 6. A method according to claim 1 wherein in the compound offormula I:R¹ is 2-adamantyl or 1-(S)-2-endobornyl; A is --NHCO--,--OCO--, --SO₂ --, --S(═O)-- or --CH₂ CO--; R² is --CH₃, --CH₂ CO₂ H or--CH₂ C.tbd.CH R³ is --(CH₂)_(n),--B--D or H; R⁴ is --(CH₂)_(n) --B--Dor H; and R⁹ is hydrogen or methyl.
 7. A method according to claim 1wherein in the compound of formula I:R¹ is 2-adamantyl,1-(S)-2-endobornyl, or 2-methyl cyclohexyl ; A is --OC(═O)--; R² is--CH₃ ; R³ is H, CH₂ OH, CH₂ OCOCH₂ CH₂ CO₂ H, CH₂ OCOCH═CHCO₂ H, CH₂NHCOCH₂ CH₂ CO₂ H, CH₂ NHCOCH═CHCO₂ H, or CH₂ CO₂ H; R⁴ is H, --CH₂ SCH₂CO₂ H, --CH₂ SCH₂ CH₂ CO₂ H, --NHCOCH═CHCO₂ H, --NHCOCH₂ CH₂ CO₂ H inthe (D) configuration, or NHCOCH═CHCO₂ H in the (D) configuration).
 8. Amethod according to claim 1 wherein the compound is selectedfrom:(±)-trans-2-chlorocyclohexyl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate;2-chlorocyclohexyl[2-[[1-(hydroxymethyl)-2-phenylethyl]-amino]-1-(1H-indo1-3-ylmethyl)-1-methyl-2-oxoethyl]-carbamate;2-[[2-[[[(2-chlorocyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate;2-[[2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl]amino]-3-phenylpropylbutanedioate; (±)-tricyclo[3.3.1.1³,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]-ethyl]carbamate;(+) or(-)-2-chlorocyclohexyl[1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate;tricyclo[3.3.1.1³,7]dec-2-yl[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-1-methyl-2-oxoethyl]carbamate;2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo-[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-3-phenylpropyl butanedioate;[1S-[1α,2β[S*(S*)],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoicacid;[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]amino]-4-oxo-2-butenoicacid;[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]amino]-4-oxo-butanoicacid;[R-(R*,S*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]amino]-4-oxo-butanoicacid; (R)-tricyclo[3.3.1.1³,7]dec-2-yl[1-(1H-indol-3-ylmethyl)-1-methyl-2-[methyl(2-phenylethyl)amino]-2-oxoethylcarbamate,[R-(R*,S*)]-2-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3phenylpropyl]sulfinyl]aceticacid;[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]thio]aceticacid;[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfinyl]acetic acid, ethylester;[R-(R*,S*)]-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)]carbonyl]amino]-propyl]amino]-3-phenylpropyl]sulfonyl]aceticacid;[R-[R*,R*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid;[R-(R*,S*)]-[[2-[[2-[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]-propyl]amino]-3-phenylpropyl]thio]aceticacid;[1S-[1α,2β[S*[S*(E)]],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid, methyl ester, (bicyclo system is 1S-endo);[1S-[1α,2β[S*[S*(E)]],4α]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[[(1,7,7-trimethylbicyclo-[2.2.1]hept-2-yl)oxy]carbonyl]amino]propyl]amino]-1-phenylethyl]amino]-4-oxo-2-butenoicacid (bicyclo system is 1S-endo);[R-(R*,R*)]-3-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2 -yloxy)carbonyl]amino]-propyl]amino]-1-phenylethyl]amino]-3-oxopropanoic acid;[R-(R*,S*)]-3-(1H-indol-3-ylmethyl)-3-methyl-4,10-dioxo-6-(phenylmethyl)-11-oxo-8-thia-2,5-diazatridecanoicacid, tricyclo[3.3.1.1³,7 ]-dec-2-yl or ester;[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]benzenebutanoic acid;[R-(R*,S*)]-β-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2[[(tricyclo[3.3.1.1.sup.3,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-4-iodobenzenebutanoic acid,where the iodo group may be I-125 or I-127;[R-(R*,S*)]--N-[3-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1.sup.3,7]dec-2yloxy)carbonyl]amino]-propyl]amino]-4-phenylbutyl]glycine; and[R-[R*,S*-(E)]]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-2-[[(bicyclo [3.3.1]non-9-yloxy)carbonyl]amino]-1-oxopropyl]amino]-3-phenylpropyl]amino]4-oxo-2-butenoicacid.
 9. A method of treating panic disorder in a human who has beenidentified as exhibiting panic disorder symptoms which comprisesadministering to said human a therapeutically effective amount of[R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1³,7]dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino-4-oxobutanoic acid, ora pharmaceutically acceptable salt thereof.